The Effects of the Great East Japan Earthquake on Perinatal Outcomes: Results of the Pregnancy and Birth Survey in the Fukushima Health Management Survey

There are limited studies on the long-term effects of natural/environmental disasters, especially nuclear disasters, on obstetric outcomes. This study aimed to review the results of perinatal outcomes immediately after the Great East Japan Earthquake (GEJE) and the Fukushima Daiichi Nuclear Power Plant accident, as well as their long-term trends over 8 years, in the Fukushima Health Management Survey. The annual population-based Pregnancy and Birth Survey is conducted as part of the Fukushima Health Management Survey. The Fukushima Prefecture government launched it to assess the health conditions of pregnant women and their neonates after the GEJE. The self-reported questionnaire was sent to 115,976 pregnant women by mail from January 2012, with 58,344 women responding to the questionnaire (50.3% response rate). Pregnancy complications, such as gestational hypertension, respiratory diseases, and mental disorders, increased in some women who were pregnant at the time of the earthquake and immediately after the earthquake. However, the direct effects on newborns, such as preterm birth, low birth weight, and congenital anomalies, were not immediately clear after the earthquake. Although there were significant differences in the occurrence of preterm birth and low birth weight among the districts, there was no change in the occurrences of preterm birth, low birth weight, or anomalies in newborns in Fukushima Prefecture from the fiscal year 2011 to the fiscal year 2018. Therefore, the long-term effects of the post-disaster radiation accident on perinatal outcomes are considered to be very small.


INTRODUCTION
The most devastating event in recent Japanese history is the Great East Japan Earthquake (GEJE), which occurred on Mar 11, 2011, along with the subsequent tsunami and nuclear accident at the Fukushima Daiichi Nuclear Power Plant. In the Fukushima Prefecture, thousands of deaths occurred due to the tsunami. The devastation affected many people living in the coastal areas of the Soso and Iwaki districts. After the power plant accidents, many people (including pregnant women) living in coastal areas were suddenly forced to evacuate by government order. The Aizu district, located in a mountainous region in Fukushima Prefecture far from the power plant, was hardly affected by the nuclear accident compared to the coastal regions ( Figure 1). After the disaster, Fukushima Prefecture launched the Fukushima Health Management Survey (FHMS). 1,2 This population-based study includes geographical and birth information to evaluate pregnancy outcomes and provide valuable data on the health effects of low radiation doses and disaster-related stress in 2011.
Although several studies reported the association between disaster and perinatal health, only a few studies examined perinatal health in disasters, such as Fukushima, where the earthquake, tsunami, and radiation exposure occurred in combination. 3 Few studies reported chronological trends in perinatal outcomes after the disaster. In particular, due to the concerns about radiation exposure in Fukushima, the chronological trends in pregnancy outcomes after the GEJE are of worldwide interest; the FHMS has maintained data from the investigation on the effects of this disaster on pregnancy and infant care.
This study examined the status of perinatal health in Fukushima Prefecture before and after the GEJE and their timeseries trends over 8 years by reviewing articles and reports on perinatal health surveyed by the FHMS. Based on these results, we discuss the impact of the disasters, including radiation exposure, on perinatal health in Fukushima.

Survey design
Fukushima Medical University launched the Pregnancy and Birth Survey as part of the FHMS in fiscal year (FY) 2011. 1,2,4 The survey included women who received the maternal and child health handbook between August 1 of the previous year and July 31 of the corresponding year. The maternal and child health handbook is a unique perinatal healthcare initiative in Japan. The handbook helps maintain a record of women's prenatal and postnatal checkups by physicians.

Target population
The self-reported questionnaire was sent to 115,976 pregnant women by mail between January 2012 and December 2019 (FY2011, 16

Maternal information and obstetrics outcome
The self-reported questionnaire included maternal information, such as the geographic district where the pregnant women received their maternal and child health handbook, delivery date, maternal age at delivery, single or multiple gestational pregnancies, gestational weeks at delivery, mode of pregnancy, and mode of delivery. It also included neonatal information, such as neonatal birth weight, sex of the newborn, and the presence of anomalies in the newborn. There were six classifications for the geographic district: Kenpoku, Kenchu, Kennan, Soso, Iwaki, and Aizu ( Figure 1). Soso and Iwaki are on the coastal areas of Fukushima Prefecture. Soso is nearest the nuclear power plant, and many of its residents were forced to evacuate after the nuclear accident. Kenpoku, Kenchu, and Kennan are in the center of Fukushima Prefecture. Kenpoku reportedly has relatively higher radiation levels than Kenchu and Kennan. 6,7 The Aizu region is mountainous and far from the nuclear power plant, and radiation levels are the lowest in the Prefecture. Deliveries before 37 gestational weeks were defined as preterm birth, and birth weights less than 2,500 g were defined as low birth weight. 8 The mode of pregnancy was categorized as natural pregnancy or fertility treatment, such as ovulation induction, artificial insemination, and in vitro fertilization. The mode of delivery was categorized as vaginal delivery or caesarian section. The following major anomalies were reported in the newborns: cataracts, cardiac malformation, kidney, and urinary tract malformation, spina bifida, microcephaly, hydrocephalous, cleft lip and palate, intestinal atresia (esophagus, duodenum, ileum), imperforate anus, polydactylism, and syndactylism. Every anomaly reported on the questionnaire was defined as a major anomaly.

Ethical considerations
The local ethics review committee of the author's institution approved this study (Approval No. 1317), and all participants provided written informed consent.

RESULTS
The incidence of pregnancy complications among pregnant women during the disaster We report pregnancy complications among pregnant women during the disaster using the results of the FHMS, which targeted women who gave birth during 2011-2012. Pregnant women were divided into four groups according to pregnancy trimester during the disaster (first, second, third trimester, or conception after the disaster). As a result, the third trimester of pregnancy at the time of the disaster was associated with hypertensive pregnancy disorder for the women living in the areas most exposed to the disaster. 9 Data from 12,300 women who became pregnant in Fukushima Prefecture in the 9 months before and after the disaster were collected and analyzed. 10 The results showed no obstetric-related adverse events among the women who became pregnant in the 9 months before the disaster. 10 In contrast, there was an increased incidence of medical complications, such as respiratory diseases and mental disorders, among the women who became pregnant within 6 months of the earthquake ( Figure 2). 10 Suzuki et al examined the association between changes in medical institutions for perinatal care and gestational duration after the GEJE in 5,593 survey participants. They experienced the earthquake between the fourth and 37th weeks of their gestational period. 11 The results showed that pregnant women who changed perinatal checkup institutions due to medical indications had a Obstetrics Outcomes After the Great East Japan Earthquake significantly shorter gestation duration and more preterm births than those who visited only one institution. However, selfreferral, which could indicate post-disaster relocation, was not significantly associated with shorter gestation and preterm birth, 11 suggesting that the GEJE and the subsequent accident at the Fukushima Daiichi Nuclear Power Plant did not have a direct impact on gestational duration.
The incidence of stillbirth, preterm birth, low birth weight, and congenital anomalies during the disaster In Fukushima Prefecture during the first year after the disaster, the incidence rates for stillbirth (over 22 completed gestational weeks), preterm birth, low birth weight, and congenital anomalies were 0.25%, 4.4%, 8.7%, and 2.72%, respectively. 4 These rates are similar to rates recently reported elsewhere in Japan. There were no significant differences in the incidence rate of stillbirth or preterm birth among the regional areas, while the incidence rate of low birth weight varied; that of Iwaki was the highest (10.6%) and Kenpoku was the lowest (7.6%). 4 There were no significant differences in the incidence rate of all congenital anomalies among the regional area (P for difference = 0.275), although the rate of Kennan was somewhat higher than other regional areas ( Figure 3). 4 The analysis of the same 12,300 participants as above showed an increased incidence of low birth weight (<1,500 g and <2,500 g) and preterm birth among women who became pregnant within 6 months of the earthquake (Figure 4 and Figure 5). 10 We also evaluated the incidence and obstetric outcomes of women who became pregnant using assisted reproductive technology procedures in Fukushima Prefecture and reported that the impact of the disaster was minimal. The proportion of women who became pregnant using in vitro fertilization and embryo transfer decreased during the first 2 months after the earthquake. It returned to pre-disaster levels in the third month after the earthquake. For women who became pregnant without in vitro fertilization and embryo transfer, the incidence of preterm birth and low birth weight increased after the earthquake. 12 The incidence rate for small for gestational age (SGA) status among newborns delivered by women who were pregnant at the time of the disaster in Fukushima Prefecture was 5.6% (325 of 5,790). 13 The regional proximity to the disaster and gestational age did not affect the incidence of SGA. In the multivariate analysis, gestational hypertension (also known as pregnancyinduced hypertension) was higher in the SGA group and was an independent risk factor for SGA. 13 Trends in preterm birth, low birth weight, and congenital anomalies from FY2011 to FY2018 Figure 6 shows the trends in preterm birth, low birth weight, and congenital anomalies from FY2011 to FY2018. 5 There was no change in incidence rate of preterm birth, low birth weight, and congenital anomalies during the survey period. The incidence of    preterm births and low birth weight ranged from 4.8% to 5.8% and from 8.9% to 10.1%, respectively, during the survey period. Meanwhile, 5.7% and 9.4% of births nationwide were reported as preterm births and low birth weight, respectively, according to the 2017 Vital Statistics, and the survey results in Fukushima were similar to the national results. The incidence of congenital anomalies ranged from 2.19% to 2.85% during the survey period.
Since the general incidence of congenital anomalies is reported to be 3% to 5%, the incidence in Fukushima was considered to be equal to or lower than these values.

DISCUSSION
The Pregnancy and Birth Survey of the Fukushima Health Management Survey is the first population-based survey to examine the long-term trends of perinatal outcomes among pregnant women in Fukushima Prefecture after the disaster. This survey revealed that pregnancy complications, such as gestational hypertension, respiratory diseases, and mental disorders, increased in some women who were pregnant at the time of the earthquake and immediately after the earthquake. However, the Before the disaster 4-6 months Before the disaster ≤3 months After the disaster ≤3 months After the disaster 4-6 months After the disaster 7-9 months *P<0.05, in relation to 7-9 months before the disaster group. **P<0.05, in relation to ≤3 months before the disaster group. * ** Figure 4. Incidence rate of low birth weight in the pregnant women before and after the disaster. * P < 0.05, in relation to 9-7 months before the disaster group. ** P < 0.05, in relation to :3 months before the disaster group. Before the disaster 7-9 months Before the disaster 4-6 months Before the disaster ≤3 months After the disaster ≤3 months After the disaster 4-6 months After the disaster 7-9 months * Figure 5. Incidence rate of preterm birth among the pregnant women before and after the disaster. * P < 0.05, in relation to :3 months before the disaster group.
Preterm birth Low birth weight (<2500 g) Congenital anomalies Figure 6. Trends in incidence rate of preterm birth, low birth weight, and congenital anomalies from FY 2011 to FY 2018 Obstetrics Outcomes After the Great East Japan Earthquake direct effects on newborns, such as preterm birth, low birth weight, and congenital anomalies, were unclear, either immediately after the earthquake or for several years after the earthquake. Furthermore, there is no association between radiation exposure dose and perinatal outcomes. 14 Therefore, we can conclude that there is no evidence of a direct effect of radiation exposure on perinatal outcomes due to the radiation accident of Fukushima Prefecture. Disasters potentially influence a range of reproductive outcomes. 15 Numerous studies examined the effects of exposure to disasters on pregnancy outcomes, such as the World Trade Center Disaster, the bombing attacks in Serbia, and the Madrid train bombing; environmental and chemical disasters, such as the Bhopal gas release in India, the Three Mile Island accident, and the Chernobyl accident; and natural disasters, such as earthquakes, hurricanes, floods, and ice streams. 3 The GEJE and Fukushima Daiichi nuclear accidents formed a complex disaster because they included the natural disaster of the Great Earthquake and tsunami and the environmental/technical disaster of the nuclear power plant accident. However, the Japan Environment and Children's Study conducted in Fukushima Prefecture examined perinatal outcomes using the results of 12,804 births in the prefecture between 2011 and 2014. 16 The prevalence of preterm birth, low birth weight, and neonatal anomalies were 5.6%, 9.5%, and 1.7%, respectively, 16 which were not so different from the results of our study.

Fukushima disaster and preterm birth and low birth weight
There are conflicting findings on the association between environmental/chemical disasters and gestational age and birth weight. Goldman et al reported that the Love Canal disaster in the United States showed no significant association with gestational age among 227 residents. 17 However, Levi et al reported that the Chernobyl accident affected gestational age and maternal anxiety among 88 Swedish women early in their pregnancy at the time of the disaster. 18 In contrast to our study, an earthquake disaster in China increased the risk of preterm birth. Tan et al compared the incidence of preterm birth between 6,638 pregnant women before the disaster and 6,365 pregnant women after. 19 The incidence of preterm birth was 5.6% and 7.4%, respectively, which was significantly higher after the disaster (P < 0.01). In Japan, the incidence of high-risk pregnancies has increased due to advanced maternal age and complicated pregnancies 20,21 ; the post-disaster incidence rates of preterm birth <37 gestational weeks (5.7%) and low birth weight <2,500 g (9.4%) 22 have been almost stable.
Several studies have reported that environmental and natural disasters increase the risk of low birth weight. [23][24][25] However, several studies have reported no effect of these disasters on birth weight. 17,26 With regard to the GEJE and Fukushima Daiichi nuclear accident, we reported that there was no evidence that the disaster increased the incidence of SGA births in Fukushima Prefecture during the 8 years after the disaster. Using an institutional investigation in a coastal area where the maximum catastrophic damage had occurred in the GEJE, 27 Leppold et al reported no marked increase in the proportion of preterm birth and low birth weight in any year after the disaster (merged postdisaster risk ratio of preterm birth: 0.68; 95% confidence interval [CI], 0.38-1.21 and low birthweight: 0.98; 95% CI, 0.64-1.51). 27 In Japan, pregnant women could have better access to relief programs or might receive adequate support from their family, society, and the government during disasters. 28 Although the effects on newborns are unclear, it has been reported that the proportion of pregnant women with depressive symptoms increased after the GEJE due to the sudden evacuation of numerous pregnant women and the drastic changes in their living environment. [28][29][30] Therefore, we need to continue examining the direct effects of the earthquake and radiation accident and the indirect effects, such as long-term evacuation.

Fukushima disaster and congenital anomalies
The association between disasters and congenital anomalies is a major public concern. Several major environmental and technical disasters have been related to congenital anomalies, including the nuclear reactor accidents at Chernobyl in 1986 and Three Mile Island in 1979. The accident at Chernobyl involved a much larger radiation dose exposure and affected more people than the Three Mile Island and Fukushima incidents. Reviews on the effect of the Chernobyl disaster indicated increased microcephaly and neural tube defects. [31][32][33] However, the incidence of most congenital disabilities did not increase in most European countries. [34][35][36] It was widely reported that 2-3% of all newborns have a major congenital abnormality that is detectable at birth. 37,38 From 2011 to 2016, the incidence of congenital disabilities in Japan was 2.43-2.59%, according to a report of the International Clearinghouse for Birth Defects Surveillance and Research Japan Center, 39 although this has not increased since the GEJE. Using the Japanese birth cohort study that included 12,804 pregnant women in Fukushima Prefecture, Kyozuka et al reported that the prevalence of major congenital anomalies at delivery between 2011 and 2014 in the prefecture was 1.6% to 3.2%, depending on maternal age, 16 and these rates were similar to the national rates.
Nevertheless, a survey of hospital discharge records for cryptorchidism showed an increased discharge rate for cryptorchidism nationwide after the GEJE. 40 However, Kojima et al reported that it is difficult to clarify cryptorchidism prevalence because of complexities in design settings for epidemiological surveys of this disease. They rejected the hypothesis that cryptorchidism increased in Japan due to the Fukushima Daiichi Nuclear Power Plant accident. 41 Hirai et al, employing the All Japanese Cardiovascular Surgery Database, revealed no increase in the number of patients with congenital heart disease from 2010 to 2013. 42

Strengths and limitations
The Pregnancy and Birth Survey has several strengths. In Japan, few epidemiological studies involve pregnant women in a community. Large-scale studies and data supported by the government are considered valuable. In addition, we obtained relatively accurate data on gestational ages and birth weights from the participants from their maternal and child health handbook. Nevertheless, the survey has potential limitations. First, the response rate was only approximately 50-60% throughout the study period. Therefore, the actual incidence of negative outcomes could have been overestimated if there was an overrepresentation of women affected the most by the disasters, especially those who were pregnant between 2011 and 2012. Second, given that this study used a self-administered questionnaire, we assume that the mothers answered correctly, especially regarding fetal anomalies. Kyozuka H, et al.

Conclusion
In conclusion, the results of the Pregnancy and Birth Survey indicate that the effects of GEJE and the subsequent nuclear accident on pregnant women are negligible in the long term. Improving the understanding of the adverse reproductive effects of disasters requires as much preparedness as required for the emergency response to prevent mortality and morbidity. Further studies should examine whether the disaster caused psychological complications or early pregnancy loss, such as miscarriage and abortion. Due to the relatively high incidence of anxiety and potential long-lasting negative effects on the mental and physical health of mothers, their children, and even other family members, the findings of the Pregnancy and Birth Survey could have significant public health implications.

ACKNOWLEDGMENTS
This survey was partially supported by the National Health Fund for Children and Adults Affected by the Nuclear Incident. The findings and conclusions of this article are solely the authors' responsibility and do not represent the government's official views of Fukushima Prefecture. Editorial support, in the form of medical writing based on authors' detailed directions, collating author comments, copyediting, fact-checking, and referencing, was provided by Cactus Communications. The local ethics review committee of the authors' institution approved this survey (Approval No. 1317).
Funding: The National Health Fund for Children and Adults Affected by the Nuclear Incident.
Conflicts of interest: None declared.